WO03/066635 describes a number of diazabicycle derivatives having NK1 activity, including the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (otherwise known as orvepitant).
The structure of the 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxo-hexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)-piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (otherwise known as orvepitant) is shown in formula (I) below:

Hereinafter any reference to orvepitant refers to the compound of formula (I). Orvepitant may also be known as:
CAS Index Name
    1-Piperidinecarboxamide, N-[(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]-2-(4-fluoro-2-methylphenyl)-4-[(8aS)-hexahydro-6-oxopyrrolo[1,2-a]pyrazin-2(1H)-yl]-N-methyl-, (2R,4S) andIUPAC Name:    (2R,4S)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-piperidinecarboxamide.
A preferred salt of this compound is its hydrochloride salt which is otherwise known as orvepitant hydrochloride.
A further preferred salt of this compound is its maleate salt which is otherwise known as orvepitant maleate.
Particularly Example 11C of WO03/066635 describes the synthesis of orvepitant maleate using substantially the same experimental conditions described in the Example 1 in the present patent application.
We have now found that orvepitant maleate can be obtained in a new crystalline form. In particular, we have discovered a form of orvepitant maleate which is anhydrous and crystalline and which surprisingly has particularly good pharmaceutical properties. This is particularly stable and essentially non hygroscopic. It also has good storage properties and can be readily formulated into pharmaceutical compositions such as tablets and capsules.
The processes for the preparation of the anhydrous crystalline form of the present invention also show a high degree of robustness, an advantage for a highly regulated compound. Batches of this crystalline form can, by the processes of this invention, be made consistently to a high crystal form purity i.e., where the proportion of solvated and other anhydrous crystalline forms of orvepitant maleate is limited (particularly less than 10%, more particularly less than 5% and still more particularly less than 3%).
Polymorphism is defined as the ability of an element or compound to crystallise in more than one distinct crystalline phase. Thus polymorphs are distinct solids sharing the same molecular formula, however since the properties of any solid depends on its structure, different polymorphs may exhibit distinct physical properties such as different solubility profiles, different melting points, different dissolution profiles, different thermal and/or photostability, different shelf life, different suspension properties and different physiological absorption rate. Inclusion of a solvent in the crystalline solid leads to solvates, and in the case of water as a solvent, hydrates.
Polymorphic forms of a compound may be distinguished from one another and from an amorphous phase of the compound by methods including but not limited to X-ray powder diffraction (XRD), infra-red spectroscopy (IR), Raman spectroscopy, differential scanning calorimetry (DSC) and solid state nuclear magnetic resonance (ssNMR).